US6222032B1 - Use of ylides of phosphorus as slightly nuceophilic strong bases - Google Patents
Use of ylides of phosphorus as slightly nuceophilic strong bases Download PDFInfo
- Publication number
- US6222032B1 US6222032B1 US09/423,269 US42326999A US6222032B1 US 6222032 B1 US6222032 B1 US 6222032B1 US 42326999 A US42326999 A US 42326999A US 6222032 B1 US6222032 B1 US 6222032B1
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- United States
- Prior art keywords
- carbon atoms
- group
- alkyl
- alkoxy
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title description 8
- 229910052698 phosphorus Inorganic materials 0.000 title description 8
- 239000011574 phosphorus Substances 0.000 title description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 41
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 19
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 230000008569 process Effects 0.000 claims abstract description 17
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 14
- 238000007126 N-alkylation reaction Methods 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 4
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 9
- 239000001257 hydrogen Substances 0.000 claims abstract 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract 3
- 229910052717 sulfur Chemical group 0.000 claims abstract 3
- 239000011593 sulfur Chemical group 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- -1 dimethylamino, ethylmethylamino Chemical group 0.000 claims description 37
- 239000002585 base Substances 0.000 claims description 29
- 229920000642 polymer Polymers 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 8
- 229940049706 benzodiazepine Drugs 0.000 claims description 7
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 4
- 108010038807 Oligopeptides Proteins 0.000 claims description 3
- 102000015636 Oligopeptides Human genes 0.000 claims description 3
- 239000002262 Schiff base Substances 0.000 claims description 3
- 150000004753 Schiff bases Chemical class 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 2
- 150000003951 lactams Chemical class 0.000 claims 2
- 229920002223 polystyrene Polymers 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229920000058 polyacrylate Polymers 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 238000013019 agitation Methods 0.000 description 8
- 0 *CC1=CC=C(C(CC(C)C2=CC=CC=C2)CC(CC)C2=CC=CC=C2)C=C1 Chemical compound *CC1=CC=C(C(CC(C)C2=CC=CC=C2)CC(CC)C2=CC=CC=C2)C=C1 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- NAOGEBIWFZMBKH-UHFFFAOYSA-N CC(C)=P(C)(C)C Chemical compound CC(C)=P(C)(C)C NAOGEBIWFZMBKH-UHFFFAOYSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 238000005574 benzylation reaction Methods 0.000 description 4
- 150000002357 guanidines Chemical class 0.000 description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ABJCRQAARXIGEB-UHFFFAOYSA-N C.C.C.C.CN(C)C Chemical compound C.C.C.C.CN(C)C ABJCRQAARXIGEB-UHFFFAOYSA-N 0.000 description 3
- KHRIPQMMFOGLOF-UHFFFAOYSA-N C.CN(C)C Chemical compound C.CN(C)C KHRIPQMMFOGLOF-UHFFFAOYSA-N 0.000 description 3
- MPPUESUSJYVFFQ-UHFFFAOYSA-N CC(C)[PH](C)(C)C.[Y] Chemical compound CC(C)[PH](C)(C)C.[Y] MPPUESUSJYVFFQ-UHFFFAOYSA-N 0.000 description 3
- NYSBSQCGAIFRHV-UHFFFAOYSA-N CCC(CC(CC(C)C1=CC=CC=C1)c1ccc(C)cc1)C1=CC=CC=C1 Chemical compound CCC(CC(CC(C)C1=CC=CC=C1)c1ccc(C)cc1)C1=CC=CC=C1 NYSBSQCGAIFRHV-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 2
- HBAHZZVIEFRTEY-UHFFFAOYSA-N 2-heptylcyclohex-2-en-1-one Chemical compound CCCCCCCC1=CCCCC1=O HBAHZZVIEFRTEY-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VJYBRHNQHNSGBC-UHFFFAOYSA-N CC(C)[Y] Chemical compound CC(C)[Y] VJYBRHNQHNSGBC-UHFFFAOYSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 229920001367 Merrifield resin Polymers 0.000 description 2
- ZRWPUFFVAOMMNM-UHFFFAOYSA-N Patulin Chemical compound OC1OCC=C2OC(=O)C=C12 ZRWPUFFVAOMMNM-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 229920002627 poly(phosphazenes) Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000010414 supernatant solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MDUQQNWSTJAPCW-UHFFFAOYSA-N (ethyl-$l^{2}-azanyl)ethane Chemical compound CC[N]CC MDUQQNWSTJAPCW-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- HWJXOPUFKWKFTF-UHFFFAOYSA-N C.C.CC(O)C1N=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N(C)C1=O.CN1C(=O)CN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 Chemical compound C.C.CC(O)C1N=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N(C)C1=O.CN1C(=O)CN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 HWJXOPUFKWKFTF-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N CN(C)C Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- QTMAGXUZHGZJQH-UHFFFAOYSA-N CN1C(=O)CN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2.[H]C1(Cc2ccccc2)N=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N(C)C1=O Chemical compound CN1C(=O)CN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2.[H]C1(Cc2ccccc2)N=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N(C)C1=O QTMAGXUZHGZJQH-UHFFFAOYSA-N 0.000 description 1
- LLUPPOIMABPEKS-UHFFFAOYSA-N CN1CCC(CC2=CC=CC=C2)C1=O.CN1CCCC1=O Chemical compound CN1CCC(CC2=CC=CC=C2)C1=O.CN1CCCC1=O LLUPPOIMABPEKS-UHFFFAOYSA-N 0.000 description 1
- YWWDBCBWQNCYNR-UHFFFAOYSA-N CP(C)C Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- HIFDVPRIMGJOHN-UHFFFAOYSA-L O=C1CN=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N1[RaH].[H]C1([Rb])N=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N([RaH])C1=O Chemical compound O=C1CN=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N1[RaH].[H]C1([Rb])N=C(C2=CC=CC=C2)C2=C(C=CC(Cl)=C2)N([RaH])C1=O HIFDVPRIMGJOHN-UHFFFAOYSA-L 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000002720 diazolyl group Chemical group 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- NGCRXXLKJAAUQQ-UHFFFAOYSA-N undec-5-ene Chemical compound CCCCCC=CCCCC NGCRXXLKJAAUQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
- C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D227/08—Oxygen atoms
- C07D227/087—One doubly-bound oxygen atom in position 2, e.g. lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
- C07K1/082—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing phosphorus
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/40—Introducing phosphorus atoms or phosphorus-containing groups
Definitions
- the present invention relates to the use of phosphorus ylides as slightly nucleophilic strong bases.
- the invention also relates to new phosphorus ylides and their preparation.
- Phosphorus ylides were studied by Wittig in the 1950's (Johnson, A. W., 1993, Series, Editor, Ylides and Imines of phosphorus , Wiley & Wiley: New York). These molecules are quite simple and even if some are presented as colorants (U.S. Pat. No. 3,274,228), they are usually prepared to be used for Wittig's reaction (U.S. Pat. Nos. 3,681,428, 3,725,365) where their strong nucleophilic action is involved. But these compounds have never been used as bases in organic synthesis, and a fortiori as slightly nucleophilic strong bases.
- the strong neutral organic bases known to date are essentially proton sponges (Alder, R. et al., J. Chem. Soc. Chem. Commun., 1968, 723), guanidines, phosphatranes and polyphosphazenes.
- Guanidines constitute the class of strong organic bases most frequently used in organic synthesis. The best known are DBN (1,5-diazabicyclo [4.3.0] non-5-ene) and DBU (1,8-diazabicyclo [4.3.0] undec-5-ene). Other guanidines are also mentioned in the literature (Oediger, H. et al., Synthesis, 1972, 593; Schwesinger, R., Angew. Chem. Int. Ed. Eng., 1987, 26, 1164). These bases are used in elimination reactions or in oligomerization or polymerization processes as a reaction initiator (Oediger, H. et al., Synthesis, 1972, 593; Wöhrle, D. et al., Dyes and Pigments, 1992, 18, 91).
- Phosphatranes are more recent compounds (Verkade, J., 1991, Phosphatranes as proton abstracting reagents , U.S. Pat. No. 5,051,533). Their basicity is much greater than that of guanidines, which extends their field of application. The drawback of such phosphines lies in the difficulty in obtaining them and their purification.
- Alkaline bases such as BuLi, LiHMDS, NaHMDS, LDA also represent another large family of bases. They are often used with good yields to functionalize lactames, ketones or Schiff bases (Stork, G. et al., J. Org. Chem., 1976, 41, 3491; Myers, A. et al., J. Am. Chem. Soc., 1994, 116, 9361; Myers, A. et al., J. Am. Chem. Soc., 1995, 117, 8488; Yaozhong, J. et al., Synth.
- the problem is therefore to find slightly nucleophilic strong bases, which are easy to synthesize and at a low cost, which would be susbstituted on the one hand for commonly used bases which are too nucleophilic and on the other hand for recent bases which are too expensive.
- the invention therefore relates to the use of products of general formula I′
- R′ 1 , R′ 2 and R′ 3 represent, independently, a lower alkoxy or amino radical of formula R′R′′N in which R′ and R′′ independently represent one of the following radicals, non-substituted or substituted (by one or more identical or different substituents): lower alkyl, lower alkoxy, cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is a halogen atom or a lower alkyl, lower alkoxy, cyano, nitro or dialkylamino radical;
- R′ 4 represents the hydrogen atom, a lower alkyl radical or lower alkoxy
- R′ 5 represents the hydrogen atom, a lower alkyl radical, lower alkoxy or a polymeric support
- halogen represents a fluorine, chlorine, bromine or iodine atom, preferably chlorine or bromine.
- the expression lower alkyl represents a linear or branched alkyl radical having 1 to 6 carbon atoms and in particular an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals.
- the lower alkoxy radicals can correspond to the alkyl radicals indicated above.
- the linear radicals there can be mentioned the methoxy, ethoxy, propyloxy, n-butyloxy or n-hexyloxy radicals.
- the branched alkoxy radicals there can be mentioned the isopropyloxy, sec-butyloxy, isobutyloxy, ter-butyloxy, isopentyloxy, neopentyloxy or ter-pentyloxy radicals.
- cycloalkyl includes any non-aromatic cyclic hydrocarbon fragment having 3 to 10 carbon atoms and preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- aryl designates radicals which are unsaturated, monocyclic or constituted by condensed rings, carbocyclic or heterocyclic, it being understood that the heterocyclic radicals can include one or more identical or different heteroatoms chosen from oxygen, sulphur or nitrogen.
- Examples of such groups include the phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, thiatriazolyl, oxazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzaxozolyl, indolyl, purinyl, naphthyl, thionaphthyl, phenanthrenyl, anthracenyl, biphenyl, indenyl, quinolyl, isoquinolyl or quinolizinyl radicals.
- the lower arylalkyl radicals designate the radicals in which the aryl and lower alkyl radicals respectively are as defined above such as for example benzyl, phenethyl or naphthylmethyl.
- dialkylamino represents the amino radical substituted by two alkyl radicals, identical or different, as defined above, such as for example dimethylamino, (methyl)(ethyl)amino, diethylamino.
- slightly nucleophilic means non nucleophilic with respect to other centres than protons.
- strong base corresponds to the term commonly used by a person skilled in the art in the technical field considered.
- the polymeric support can be, for example, of methacrylic, acrylic or styrenic type.
- the invention relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′ as defined above characterized in that R′ 1 , R′ 2 and R′ 3 represent, independently, an amino radical of formula RR′N as defined above.
- R′ 1 , R′ 2 and R′ 3 represent, independently, the dimethylamino, (methyl)(ethyl)amino or diethylamino radical.
- the invention relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′as defined above characterized in that R′ 4 represents the hydrogen atom or an alkyl radical.
- R′ 4 represents the hydrogen atom or the methyl or ethyl radical.
- the invention also relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′as defined above characterized in that R′ 5 represents an alkyl radical, and preferably methyl, or a polymeric support.
- R′ 5 represents an alkyl radical, and preferably methyl, or a polymeric support.
- the polymeric support R′ 5 is of methacrylic type, acrylic type such as the expansine® polymer, or polystyrenic type.
- the polymeric support of polystyrenic type is of general formula (s)
- n i , m i and q i are integers greater than or equal to one.
- the polymeric support of formula (s) can originate from the corresponding polymer of formula (p)
- n, n′, m are integers greater than or equal to one and X represents a parting group.
- X can be, for example, a halogen atom, the oxycarbonyl, oxysulphonyl or oxyboronyl radical.
- the polymeric support R′ 5 originates from a polystyrenic polymer of general formula (p) as defined above in which X represents the chlorine atom and m is equal to 1, and more particularly Merrifield resin.
- a more particular subject of the invention is the use of the compounds of formula I′ as defined above, as slightly nucleophilic strong bases in N-alkylation reactions such as, for example, the N-alkylation reactions of lactames, succinimides, oligopeptides and benzodiazepines.
- a more particular subject of the invention is also the use of the products of general formula I′ as defined above as slightly nucleophilic strong bases in C-alkylation reactions such as, for example, the C-alkylation reactions of lactames, succinimides, Schiff bases and benzodiazepines.
- a subject of the invention is also new phosphorus ylides and more particularly the products of general formula (I)
- R 1 , R 2 and R 3 represent, independently, a lower alkoxy or amino radical of formula R′R′′N in which R′ and R′′ independently represent one of the following radicals, non-substituted or substituted (by one or more identical or different substituents): lower alkyl, lower alkoxy, cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is a halogen atom or a lower alkyl, lower alkoxy, cyano, nitro or dialkylamino radical;
- R 4 represents the hydrogen atom, a lower alkyl or lower alkoxy radical
- R 5 represents a polymeric support.
- R 1 , R 2 and R 3 represent, independently, an amino radical of formula RR′N as defined above.
- R 1 , R 2 and R 3 represent, independently, the radical dimethylamino, (methyl)(ethyl)amino, diethylamino radical.
- a more particular subject of the invention is the products of general formula I as defined above characterized in that R 4 represents the hydrogen atom.
- a more particular subject of the invention is the products of general formula I as defined above characterized in that the polymeric support R 5 is of methacrylic type, acrylic type such as the polymer expansine®, or polystyrenic type.
- the polymeric support of polystyrenic type is of general formula (s) as defined above.
- a subject of the invention is also a process for the preparation of the products of general formula I as defined above, characterized in that
- the preparation of compound (3), from compounds (1) and (2) is preferably carried out under an inert atmosphere, such as for example under an argon atmosphere, in a polar solvent such as 1,2-dichloroethane, acetonitrile, dimethoxyethane or diethoxymethane.
- Compound (2) is in general in stoechiometric excess with respect to compound (1).
- Y is such that Y ⁇ represents any anion known to a person skilled in the art such as, for example, halides, triflate.
- the reaction medium is then agitated under reflux of the solvent. After the standard washing stages, compound (3) is dried under vacuum. In order to obtain product (I), product (3) thus obtained is treated, at ambient temperature, in the presence of a strong base.
- the strong base can be for example a lithiated base such as alkyl lithium compounds, and more particularly butyllithium, a sodium or potassium hydride, an amide or an alcoholate.
- the solvent can be chosen from pentane, ether, tetrahydrofuran, dimethoxyethane or diethoxymethane, in which solvent the strong base is stable. The mixture obtained is agitated for a few hours. Polymer (I) is washed under vacuum then dried. It can then be used directly without further purification.
- the compound of formula (1) in which R 4 does not represent the hydrogen atom can be obtained by reacting the corresponding compound (I) in which R 4 represents the hydrogen atom, with a compound of formula R 4 X′ in which X′ represents a halogen atom and R 4 is as defined above but does not represent the hydrogen atom, at a temperature comprised between ⁇ 10 and +10° C., preferably at 0° C., in a solvent such as THF. After filtration and washing, the product thus obtained can be treated with a strong base in order to obtain the desired compound (I).
- a subject of the invention is also, as new industrial products, and in particular as new industrial products intended for the preparation of products of formula (I), the products of formula (3) as described above.
- the compounds of formula (1) and (2) are generally commercial products and can be obtained according to standard methods known to a person skilled in the art.
- the compounds of formula (I′) in which R′ 5 represents the hydrogen atom, a lower alkyl or lower alkoxy radical, can be prepared according to standard methods known to a person skilled in the art (Johnson, A. W., 1993, Series, Editor, Ylides and Imines of phosphorus , Wiley & Wiley: New York).
- the grafting rate is checked by the reactivity of the polymer obtained.
- the solvent used for the grafting can also be dimethoxyethane.
- NMR 13 C (CDCl 3 ): 37.95 (s, CH—CH 2 Ph); 49.95 (s, N—CH 2 Ph); 65.27 (s, CH—CH 2 Ph); 123,92-131.24 (s, CH arom ); 129.43, 131.99, 136.27, 137.94, 138.99, 140.05 (s, Cq); 167.43; 169.05 (s, CO and CN).
- NMR 13 C (CDCl 3 ):28.14 (s, CH 3 ); 37.80 (s, C H 2 COOtBu); 50.28 (s, N—CH 2 Ph); 60.62 (s, CH); 80.70 (s, Cq(CH 3 ) 3 ); 124,01-131.38 (s, CH arom ); 129.54; 132.11; 136.20; 137.90; 140.31 (s, Cq); 167.50; 169.02; 171.30 (s, CO, CN and COO).
- NMR 13 C (CDCl 3 ): 17.32 (s, CH 3 ); 49.82 (s, CH 2 Ph); 58.81 (s, CH); 123,94-131.30 (s, CH arom ); 130.38; 131.07; 136.39; 137.93; 140.20 (s, Cq); 167.16; 170.35 (s, CO and CN).
- NMR 13 C (CDCl 3 ): 35.28 (s, N—CH 3 ); 38.10 (s, CH 2 Ph); 65.27 (s, CH); 122,77-131.45 (s, CH arom ); 129.16; 130.32; 138.15; 139.21; 142.15 (s, Cq); 168.01; 170.05 (s, CO and CN).
- NMR 13 C (CDCl 3 ): 28.12 (s, CH 3 ); 35.21 (s, N—CH 3 ); 37.91 (s, CH 2 ); 60.56 (s, CH); 80.59 (s, C q (CH 3 ) 3 ); 122,83-130.36 (s, CH arom ); 131.52; 137.97; 139.40; 142.20 (s, C q ); 167.20; 169.70; 171.25 (s, CO, CN and COO).
- NMR 13 C (CDCl 3 ): 17.43 (s, CH 3 ); 35.15 (s, N—CH 3 ); 58.90 (s, CH); 122,59-130.54 (s, CH arom ); 129.11; 129.63; 131.38; 138.13 (s, Cq); 166.85; 171.21 (s, CO and CN).
- NMR 13 C (CDCl 3 ): 27.90; 28.06 (s, CH 3 ); 7.82 (s, CH 2 ); 50.81 (s, N—CH 2 ); 60.33 (s, CH); 80.61; 82.43 (s, Cq(CH 3 ) 3 ); 123,02-131.64 (s, CH arom ); 129.89; 130.60; 130.98; 138.08 (s, Cq); 67.39; 167.76; 170.92 (s, CO, CN and COO).
- NMR 13 C (CDCl 3 ): 27.79 (s, CH 3 ); 37.69 (s, CH 2 Ph); 50.77 (s, N— C H 2 COOtBu); 64.72 (s, CH); 82.33 (s, Cq(CH 3 ) 3 ); 122,69-131.45 (s, CH arom ); 130.68; 131.10; 138.10; 138.91; 141.08 (s, Cq); 167.30; 167.47; 169.49 (s, CO, CN and COO).
- NMR 13 C (CDCl 3 ): 17.16 (s, CH 3 ); 27.81 (s, CH— C H 3 ); 50.65 (s, CH 2 ); 58.46 (s, CH); 82.25 (s, Cq(CH 3 ) 3 ); 122,29-131.37 (s, CH arom ); 129.41; 130.82; 138.04; 141.18 (s, Cq); 167.04; 167.59; 170.50 (s, CO, CN and COO).
- Examples 2a and 2b can also be implemented using a supported ylide as defined in the present invention, and more particularly with a polymer of formula (a) as defined above in which m>1.
- NMR 13 C (CDCl 3 ): ⁇ 0.15 (s, CH 3 ); 53.71 (s, CH 2 ); 127,62-128.11 (s, Cq); 129,63-130 CH arom ); 169.50; 169.52 (s, CO and CN).
- NMR 13 C (CDCl 3 ): 27.65 (s, CH 3 ); 51.03 (s, CH 2 —COOtBu); 51.03 (s, CH 2 —COOtBu); 55.88 (s, CH 2 ); 83.50 (s, Cq(CH 3 ) 3 ); 123,63-131.98 (s, CH arom ); 130.23; 130.64; 137.85; 140.56 (s, C ipso ); 168.30; 170.26; 170.58 (s, CO, COO and CN).
- NMR 13 C (CDCl 3 ): 17.16 (s, CH 3 ); 27.81 (s, CH— C H 3 ); 50.65 (s, CH 2 ); 58.46 (s, CH); 82.25 (s, Cq(CH 3 ) 3 ); 122,29-131.37 (s, CH arom ); 129.41; 130.82; 138.04; 141.18 (s, Cq); 167.04; 167.59; 170.50 (s, CO, CN and COO).
- NMR 13 C (CDCl 3 ): 20.44; 22.42 (s, CH 2 ); 27.73 (s, CH 3 ); 31.72 (s, CH 2 —CO); 49.21; 49.90 (s, CH 2 —N); 82.49 (s, C(CH 3 ) 3 ); 168.59; 172.37 (s, CO).
- This example can also be implemented using a supported ylide as defined in the present invention, and more particularly with a polymer of formula (a) as defined above in which m>1.
- N-t-Boc-L-Leucine and the hydrochloride of the methyl ester of L-phenylalanine are coupled beforehand in the presence of a BrOP coupling agent in order to obtain the corresponding dipeptide.
- the monobenzylation product is obtained with a yield of 12% and the dibenzylation product is obtained with a yield of 28%. These compounds were analyzed by gas chromatography coupled with electron impact mass spectrometry.
- Example 2c The polymer of Example 2c is washed several times in a dichloromethane/acetonitrile mixture, dried under vacuum and re-used in the N-benzylation reaction of norvalium under conditions as described in Example 3a.
- the N-benzylated compound is recovered with a yield of 79%, a yield comparable to that obtained in Example 3a 3 .
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP97401142A EP0881235A1 (fr) | 1997-05-26 | 1997-05-26 | Nouveaux ylures de phosphore, leur préparation et leurs utilisations notamment en tant que bases fortes faiblement nucléophiles |
EP97401142 | 1997-05-26 | ||
PCT/FR1998/001048 WO1998054229A1 (fr) | 1997-05-26 | 1998-05-26 | Utilisation d'ylures de phosphore en tant que bases fortes faiblement nucleophiles |
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US6222032B1 true US6222032B1 (en) | 2001-04-24 |
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US09/423,269 Expired - Fee Related US6222032B1 (en) | 1997-05-26 | 1998-05-26 | Use of ylides of phosphorus as slightly nuceophilic strong bases |
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US (1) | US6222032B1 (ru) |
EP (2) | EP0881235A1 (ru) |
JP (1) | JP2002504900A (ru) |
AT (1) | ATE235520T1 (ru) |
AU (1) | AU7776598A (ru) |
CA (1) | CA2291345A1 (ru) |
DE (1) | DE69812614D1 (ru) |
NO (1) | NO995771D0 (ru) |
RU (1) | RU2205842C2 (ru) |
WO (1) | WO1998054229A1 (ru) |
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US10195210B2 (en) | 2010-11-08 | 2019-02-05 | Paion Uk Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
US10414749B2 (en) | 2013-03-04 | 2019-09-17 | Paion Uk Limited | Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester |
US10472365B2 (en) | 2006-07-10 | 2019-11-12 | Paion Uk Limited | Short-acting benzodiazepine salts and their polymorphic forms |
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US7160880B1 (en) | 1999-05-14 | 2007-01-09 | Cenes Limited | Short-acting benzodiazepines |
GB9911152D0 (en) * | 1999-05-14 | 1999-07-14 | Glaxo Group Ltd | Short-acting benzodiazepines |
FR2833602B1 (fr) * | 2001-12-14 | 2004-03-12 | Rhodia Chimie Sa | Procede de preparation de polyorganosiloxanes (pos) par polycondensation/redistribution d'oligosiloxanes, en presence d'une superbase et superbases employees |
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US3919126A (en) | 1973-08-23 | 1975-11-11 | Dow Chemical Co | Insoluble polyalkyl phosphonium salt resins having crosslinked backbone |
US4043948A (en) | 1973-08-23 | 1977-08-23 | The Dow Chemical Company | Insoluble polyalkyl phosphonium salt resins having carbon-carbon crosslinked backbone |
US4092466A (en) * | 1976-07-19 | 1978-05-30 | Nasa | Heat resistant polymers of oxidized styrylphosphine |
EP0030516A1 (en) | 1979-12-03 | 1981-06-17 | The Goodyear Tire & Rubber Company | Process for preparing primary alkyl chlorides |
EP0744393A1 (en) | 1995-05-23 | 1996-11-27 | Ethyl Petroleum Additives Limited | Process for the preparation of polyalkene-substituted succinic acylating agents in the presence of a dihelotriphenylphosphorane as catalysts |
Family Cites Families (1)
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DE1003730B (de) * | 1954-09-24 | 1957-03-07 | Basf Ag | Verfahren zur Herstellung von Yliden des Phosphors |
-
1997
- 1997-05-26 EP EP97401142A patent/EP0881235A1/fr not_active Withdrawn
-
1998
- 1998-05-26 CA CA002291345A patent/CA2291345A1/fr not_active Abandoned
- 1998-05-26 JP JP50032099A patent/JP2002504900A/ja active Pending
- 1998-05-26 EP EP98925783A patent/EP0986585B1/fr not_active Expired - Lifetime
- 1998-05-26 RU RU99128084/04A patent/RU2205842C2/ru not_active IP Right Cessation
- 1998-05-26 US US09/423,269 patent/US6222032B1/en not_active Expired - Fee Related
- 1998-05-26 WO PCT/FR1998/001048 patent/WO1998054229A1/fr active IP Right Grant
- 1998-05-26 DE DE69812614T patent/DE69812614D1/de not_active Expired - Lifetime
- 1998-05-26 AT AT98925783T patent/ATE235520T1/de not_active IP Right Cessation
- 1998-05-26 AU AU77765/98A patent/AU7776598A/en not_active Abandoned
-
1999
- 1999-11-25 NO NO995771A patent/NO995771D0/no not_active Application Discontinuation
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FR2019198A1 (ru) | 1968-09-30 | 1970-06-26 | British Petroleum Co | |
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DE2022489A1 (de) | 1969-05-09 | 1971-01-28 | British Petroleum Co | Katalysatortraeger |
US3725365A (en) | 1971-04-08 | 1973-04-03 | Dow Chemical Co | Resins with phosphorane pendant groups and process for preparing same |
US3919126A (en) | 1973-08-23 | 1975-11-11 | Dow Chemical Co | Insoluble polyalkyl phosphonium salt resins having crosslinked backbone |
US4043948A (en) | 1973-08-23 | 1977-08-23 | The Dow Chemical Company | Insoluble polyalkyl phosphonium salt resins having carbon-carbon crosslinked backbone |
US4092466A (en) * | 1976-07-19 | 1978-05-30 | Nasa | Heat resistant polymers of oxidized styrylphosphine |
EP0030516A1 (en) | 1979-12-03 | 1981-06-17 | The Goodyear Tire & Rubber Company | Process for preparing primary alkyl chlorides |
EP0744393A1 (en) | 1995-05-23 | 1996-11-27 | Ethyl Petroleum Additives Limited | Process for the preparation of polyalkene-substituted succinic acylating agents in the presence of a dihelotriphenylphosphorane as catalysts |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030220493A1 (en) * | 1997-05-12 | 2003-11-27 | Linda Jolliffe | Arylsubstituted piperazines useful in the treatment of benign prostatic hyperplasia |
US10472365B2 (en) | 2006-07-10 | 2019-11-12 | Paion Uk Limited | Short-acting benzodiazepine salts and their polymorphic forms |
US10961250B2 (en) | 2006-07-10 | 2021-03-30 | Paion Uk Limited | Short-acting benzodiazepine salts and their polymorphic forms |
US10195210B2 (en) | 2010-11-08 | 2019-02-05 | Paion Uk Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
US10342800B2 (en) | 2010-11-08 | 2019-07-09 | Paion Uk Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
US10414749B2 (en) | 2013-03-04 | 2019-09-17 | Paion Uk Limited | Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester |
Also Published As
Publication number | Publication date |
---|---|
EP0881235A1 (fr) | 1998-12-02 |
AU7776598A (en) | 1998-12-30 |
RU2205842C2 (ru) | 2003-06-10 |
ATE235520T1 (de) | 2003-04-15 |
EP0986585A1 (fr) | 2000-03-22 |
EP0986585B1 (fr) | 2003-03-26 |
JP2002504900A (ja) | 2002-02-12 |
DE69812614D1 (de) | 2003-04-30 |
NO995771L (no) | 1999-11-25 |
NO995771D0 (no) | 1999-11-25 |
WO1998054229A1 (fr) | 1998-12-03 |
CA2291345A1 (fr) | 1998-12-03 |
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